Search for Magnetic Monopoles with the MoEDAL Forward Trapping Detector in 13 TeV Proton-Proton Collisions at the LHC.

1 year 10 months ago
Related Articles

Search for Magnetic Monopoles with the MoEDAL Forward Trapping Detector in 13 TeV Proton-Proton Collisions at the LHC.

Phys Rev Lett. 2017 Feb 10;118(6):061801

Authors: Acharya B, Alexandre J, Baines S, Benes P, Bergmann B, Bernabéu J, Branzas H, Campbell M, Caramete L, Cecchini S, de Montigny M, De Roeck A, Ellis JR, Fairbairn M, Felea D, Flores J, Frank M, Frekers D, Garcia C, Hirt AM, Janecek J, Kalliokoski M, Katre A, Kim DW, Kinoshita K, Korzenev A, Lacarrère DH, Lee SC, Leroy C, Lionti A, Mamuzic J, Margiotta A, Mauri N, Mavromatos NE, Mermod P, Mitsou VA, Orava R, Parker B, Pasqualini L, Patrizii L, Păvălaş GE, Pinfold JL, Popa V, Pozzato M, Pospisil S, Rajantie A, Ruiz de Austri R, Sahnoun Z, Sakellariadou M, Sarkar S, Semenoff G, Shaa A, Sirri G, Sliwa K, Soluk R, Spurio M, Srivastava YN, Suk M, Swain J, Tenti M, Togo V, Tuszyński JA, Vento V, Vives O, Vykydal Z, Whyntie T, Widom A, Willems G, Yoon JH, Zgura IS, MoEDAL Collaboration

Abstract
MoEDAL is designed to identify new physics in the form of long-lived highly ionizing particles produced in high-energy LHC collisions. Its arrays of plastic nuclear-track detectors and aluminium trapping volumes provide two independent passive detection techniques. We present here the results of a first search for magnetic monopole production in 13 TeV proton-proton collisions using the trapping technique, extending a previous publication with 8 TeV data during LHC Run 1. A total of 222 kg of MoEDAL trapping detector samples was exposed in the forward region and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges exceeding half the Dirac charge are excluded in all samples and limits are placed for the first time on the production of magnetic monopoles in 13 TeV pp collisions. The search probes mass ranges previously inaccessible to collider experiments for up to five times the Dirac charge.

PMID: 28234515 [PubMed - in process]

Stream of consciousness: Quantum and biochemical assumptions regarding psychopathology.

1 year 10 months ago
Related Articles

Stream of consciousness: Quantum and biochemical assumptions regarding psychopathology.

Med Hypotheses. 2017 Apr;101:78-84

Authors: Tonello L, Cocchi M, Gabrielli F, Tuszynski JA

Abstract
The accepted paradigms of mainstream neuropsychiatry appear to be incompletely adequate and in various cases offer equivocal analyses. However, a growing number of new approaches are being proposed that suggest the emergence of paradigm shifts in this area. In particular, quantum theories of mind, brain and consciousness seem to offer a profound change to the current approaches. Unfortunately these quantum paradigms harbor at least two serious problems. First, they are simply models, theories, and assumptions, with no convincing experiments supporting their claims. Second, they deviate from contemporary mainstream views of psychiatric illness and do so in revolutionary ways. We suggest a possible way to integrate experimental neuroscience with quantum models in order to address outstanding issues in psychopathology. A key role is played by the phenomenon called the "stream of consciousness", which can be linked to the so-called "Gamma Synchrony" (GS), which is clearly demonstrated by EEG data. In our novel proposal, a unipolar depressed patient could be seen as a subject with an altered stream of consciousness. In particular, some clues suggest that depression is linked to an "increased power" stream of consciousness. It is additionally suggested that such an approach to depression might be extended to psychopathology in general with potential benefits to diagnostics and therapeutics in neuropsychiatry.

PMID: 28351500 [PubMed - indexed for MEDLINE]

Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma.

1 year 10 months ago
Related Articles

Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma.

Oncotarget. 2017 May 30;8(22):35639-35655

Authors: Velpula KK, Guda MR, Sahu K, Tuszynski J, Asuthkar S, Bach SE, Lathia JD, Tsung AJ

Abstract
Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism.

PMID: 28410193 [PubMed - indexed for MEDLINE]

Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism.

1 year 10 months ago
Related Articles

Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism.

BMC Neurosci. 2017 Apr 19;18(1):38

Authors: Cocchi M, Minuto C, Tonello L, Gabrielli F, Bernroider G, Tuszynski JA, Cappello F, Rasenick M

Abstract
In this paper we present a mechanistic model that integrates subneuronal structures, namely ion channels, membrane fatty acids, lipid rafts, G proteins and the cytoskeleton in a dynamic system that is finely tuned in a healthy brain. We also argue that subtle changes in the composition of the membrane's fatty acids may lead to down-stream effects causing dysregulation of the membrane, cytoskeleton and their interface. Such exquisite sensitivity to minor changes is known to occur in physical systems undergoing phase transitions, the simplest and most studied of them is the so-called Ising model, which exhibits a phase transition at a finite temperature between an ordered and disordered state in 2- or 3-dimensional space. We propose this model in the context of neuronal dynamics and further hypothesize that it may involve quantum degrees of freedom dependent upon variation in membrane domains associated with ion channels or microtubules. Finally, we provide a link between these physical characteristics of the dynamical mechanism to psychiatric disorders such as major depression and antidepressant action.

PMID: 28420346 [PubMed - indexed for MEDLINE]

Software for molecular docking: a review.

1 year 10 months ago
Related Articles

Software for molecular docking: a review.

Biophys Rev. 2017 Apr;9(2):91-102

Authors: Pagadala NS, Syed K, Tuszynski J

Abstract
Molecular docking methodology explores the behavior of small molecules in the binding site of a target protein. As more protein structures are determined experimentally using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, molecular docking is increasingly used as a tool in drug discovery. Docking against homology-modeled targets also becomes possible for proteins whose structures are not known. With the docking strategies, the druggability of the compounds and their specificity against a particular target can be calculated for further lead optimization processes. Molecular docking programs perform a search algorithm in which the conformation of the ligand is evaluated recursively until the convergence to the minimum energy is reached. Finally, an affinity scoring function, ΔG [U total in kcal/mol], is employed to rank the candidate poses as the sum of the electrostatic and van der Waals energies. The driving forces for these specific interactions in biological systems aim toward complementarities between the shape and electrostatics of the binding site surfaces and the ligand or substrate.

PMID: 28510083 [PubMed]

Ion Channel and Neurotransmitter Modulators as Electroceutical Approaches to the Control of Cancer.

1 year 10 months ago
Related Articles

Ion Channel and Neurotransmitter Modulators as Electroceutical Approaches to the Control of Cancer.

Curr Pharm Des. 2017;23(32):4827-4841

Authors: Tuszynski J, Tilli TM, Levin M

Abstract
The activities of individual cells must be tightly coordinated in order to build and maintain complex 3- dimensional body structures during embryogenesis and regeneration. Thus, one way to view cancer is within systems biology as a network disorder affecting the ability of cells to properly interact with a morphodynamic field of instructive signals that keeps proliferation and migration orchestrated toward the anatomical needs of the host organism. One layer of this set of instructive microenvironmental cues is bioelectrical. Voltage gradients among all somatic cells (not just excitable nerve and muscle) control cell behavior, and the ionic coupling of cells into networks via electrochemical synapses allows them to implement tissue-level patterning decisions. These gradients have been increasingly implicated in the induction and suppression of tumorigenesis and metastasis, in the emerging links between developmental bioelectricity to the cancer problem. Consistent with the well-known role of neurotransmitter molecules in transducing electrical activity to downstream cascades in the brain, serotonergic signaling has likewise been implicated in cancer. Here, we review these recent data and propose new approaches for manipulating bioelectric and neurotransmitter pathways in cancer biology based on a bioelectric view of cancer. To support this methodology, we present new data on the effects of the SSRI Prozac and its analog (ZINC ID = ZINC06811610) on survival of both cancer (MCF7) and normal (MCF10A) breast cells exposed to these compounds. We found an IC50 concentration (25 µM for Prozac and 100 µM for the Prozac analog) at which these compounds inhibited tumor cell survival and proliferation. Additionally, at these concentrations, we did not observe alterations in a non-tumoral cell line. This constitutes a proof-of-concept demonstration for our hypothesis that the use of both existing and novel drugs as electroceuticals could serve as an alternative to highly toxic chemotherapy strategies replacing or augmenting them with less toxic alternatives. We believe this new approach forms an exciting roadmap for future biomedical advances.

PMID: 28554310 [PubMed - indexed for MEDLINE]

A computational method for selecting short peptide sequences for inorganic material binding.

1 year 10 months ago
Related Articles

A computational method for selecting short peptide sequences for inorganic material binding.

Proteins. 2017 Nov;85(11):2024-2035

Authors: Nayebi N, Cetinel S, Omar SI, Tuszynski JA, Montemagno C

Abstract
Discovering or designing biofunctionalized materials with improved quality highly depends on the ability to manipulate and control the peptide-inorganic interaction. Various peptides can be used as assemblers, synthesizers, and linkers in the material syntheses. In another context, specific and selective material-binding peptides can be used as recognition blocks in mining applications. In this study, we propose a new in silico method to select short 4-mer peptides with high affinity and selectivity for a given target material. This method is illustrated with the calcite (104) surface as an example, which has been experimentally validated. A calcite binding peptide can play an important role in our understanding of biomineralization. A practical aspect of calcite is a need for it to be selectively depressed in mining sites.

PMID: 28734030 [PubMed - indexed for MEDLINE]

Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin.

1 year 10 months ago
Related Articles

Modeling the Colchicum autumnale Tubulin and a Comparison of Its Interaction with Colchicine to Human Tubulin.

Int J Mol Sci. 2017 Aug 02;18(8):

Authors: Spasevska I, Ayoub AT, Winter P, Preto J, Wong GK, Dumontet C, Tuszynski JA

Abstract
Tubulin is the target for many small-molecule natural compounds, which alter microtubules dynamics, and lead to cell cycle arrest and apoptosis. One of these compounds is colchicine, a plant alkaloid produced by Colchicum autumnale. While C. autumnale produces a potent cytotoxin, colchicine, and expresses its target protein, it is immune to colchicine's cytotoxic action and the mechanism of this resistance is hitherto unknown. In the present paper, the molecular mechanisms responsible for colchicine resistance in C. autumnale are investigated and compared to human tubulin. To this end, homology models for C. autumnale α-β tubulin heterodimer are created and molecular dynamics (MD) simulations together with molecular mechanics Poisson-Boltzmann calculations (MM/PBSA) are performed to determine colchicine's binding affinity for tubulin. Using our molecular approach, it is shown that the colchicine-binding site in C. autumnale tubulin contains a small number of amino acid substitutions compared to human tubulin. However, these substitutions induce significant reduction in the binding affinity for tubulin, and subsequently fewer conformational changes in its structure result. It is suggested that such small conformational changes are insufficient to profoundly disrupt microtubule dynamics, which explains the high resistance to colchicine by C. autumnale.

PMID: 28767055 [PubMed - indexed for MEDLINE]

Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

1 year 10 months ago
Related Articles

Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

PLoS One. 2017;12(8):e0182400

Authors: Wang RC, Chen X, Parissenti AM, Joy AA, Tuszynski J, Brindley DN, Wang Z

Abstract
INTRODUCTION: One of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs) are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1). In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs) than the non-resistant cells.
METHODS: Two isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.
RESULTS: MCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, but more sensitive to colchicine compared to MCF-7CC cells. PARP cleavage assay further demonstrated that all of the MTAs induced apoptosis of the MCF-7 cells. However, again, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, and more sensitive to colchicine compared to MCF-7CC cells. Live imaging demonstrated that the microtubule dynamics of MCF-7TXT cells were less sensitive to vinca alkaloids, and more sensitive to colchicine. MCF-7TXT cells were also noted to be more sensitive to other CSBAs including 2MeOE2, ABT-751 and phosphorylated combretastatin A-4 (CA-4P).
CONCLUSION: Docetaxel-resistant MCF-7TXT cells have demonstrated cross-resistance to vinca alkaloids, but appear to be more sensitive to CSBAs (colchicine, 2MeOE2, ABT-751 and CA-4P) compared to non-resistant MCF-7CC cells. Taken together these results suggest that CSBAs should be evaluated further in the treatment of taxane resistant breast cancer.

PMID: 28787019 [PubMed - indexed for MEDLINE]

Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA.

1 year 10 months ago
Related Articles

Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA.

Molecules. 2017 Aug 16;22(8):

Authors: Lepre MG, Omar SI, Grasso G, Morbiducci U, Deriu MA, Tuszynski JA

Abstract
The transcription factor p53 is a potent tumor suppressor dubbed as the "guardian of the genome" because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority are missense mutations located in the DNA binding region. Among them, G245S is known to be a structural hotspot mutation. To understand the behaviors and differences between the wild-type and mutant, both a dimer of the wild type p53 (wt-p53) and its G245S mutant (G245S-mp53), complexed with DNA, were simulated using molecular dynamics for more than 1 μs. wt-p53 and G245S-mp53 apo monomers were simulated for 1 μs as well. Conformational analyses and binding energy evaluations performed underline important differences and therefore provide insights to understand the G245S-mp53 loss of function. Our results indicate that the G245S mutation destabilizes several structural regions in the protein that are crucial for DNA binding when found in its apo form and highlight differences in the mutant-DNA complex structure compared to the wt protein. These findings not only provide means that can be applied to other p53 mutants but also serve as structural basis for further studies aimed at the development of cancer therapies based on restoring the function of p53.

PMID: 28813011 [PubMed - indexed for MEDLINE]

Response to Alternating Electric Fields of Tubulin Dimers and Microtubule Ensembles in Electrolytic Solutions.

1 year 10 months ago
Related Articles

Response to Alternating Electric Fields of Tubulin Dimers and Microtubule Ensembles in Electrolytic Solutions.

Sci Rep. 2017 Aug 29;7(1):9594

Authors: Santelices IB, Friesen DE, Bell C, Hough CM, Xiao J, Kalra A, Kar P, Freedman H, Rezania V, Lewis JD, Shankar K, Tuszynski JA

Abstract
Microtubules (MTs), which are cylindrical protein filaments that play crucial roles in eukaryotic cell functions, have been implicated in electrical signalling as biological nanowires. We report on the small-signal AC ("alternating current") conductance of electrolytic solutions containing MTs and tubulin dimers, using a microelectrode system. We find that MTs (212 nM tubulin) in a 20-fold diluted BRB80 electrolyte increase solution conductance by 23% at 100 kHz, and this effect is directly proportional to the concentration of MTs in solution. The frequency response of MT-containing electrolytes exhibits a concentration-independent peak in the conductance spectrum at 111 kHz (503 kHz FWHM that decreases linearly with MT concentration), which appears to be an intrinsic property of MT ensembles in aqueous environments. Conversely, tubulin dimers (42 nM) decrease solution conductance by 5% at 100 kHz under similar conditions. We attribute these effects primarily to changes in the mobility of ionic species due to counter-ion condensation effects, and changes in the solvent structure and solvation dynamics. These results provide insight into MTs' ability to modulate the conductance of aqueous electrolytes, which in turn, has significant implications for biological information processing, especially in neurons, and for intracellular electrical communication in general.

PMID: 28851923 [PubMed - in process]

Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction.

1 year 10 months ago
Related Articles

Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction.

Sci Rep. 2017 08 29;7(1):9877

Authors: Craddock TJA, Kurian P, Preto J, Sahu K, Hameroff SR, Klobukowski M, Tuszynski JA

Abstract
Anesthesia blocks consciousness and memory while sparing non-conscious brain activities. While the exact mechanisms of anesthetic action are unknown, the Meyer-Overton correlation provides a link between anesthetic potency and solubility in a lipid-like, non-polar medium. Anesthetic action is also related to an anesthetic's hydrophobicity, permanent dipole, and polarizability, and is accepted to occur in lipid-like, non-polar regions within brain proteins. Generally the protein target for anesthetics is assumed to be neuronal membrane receptors and ion channels, however new evidence points to critical effects on intra-neuronal microtubules, a target of interest due to their potential role in post-operative cognitive dysfunction (POCD). Here we use binding site predictions on tubulin, the protein subunit of microtubules, with molecular docking simulations, quantum chemistry calculations, and theoretical modeling of collective dipole interactions in tubulin to investigate the effect of a group of gases including anesthetics, non-anesthetics, and anesthetic/convulsants on tubulin dynamics. We found that these gases alter collective terahertz dipole oscillations in a manner that is correlated with their anesthetic potency. Understanding anesthetic action may help reveal brain mechanisms underlying consciousness, and minimize POCD in the choice and development of anesthetics used during surgeries for patients suffering from neurodegenerative conditions with compromised cytoskeletal microtubules.

PMID: 28852014 [PubMed - indexed for MEDLINE]